WO2019114066A1

WO2019114066A1 - Black phosphorus-based hydrogel near-infrared light-controllable drug release system and preparation method therefor

Info

Publication number: WO2019114066A1
Application number: PCT/CN2018/071703
Authority: WO
Inventors: 张晗; 仇萌
Original assignee: 张晗; 仇萌
Priority date: 2017-12-11
Filing date: 2018-01-08
Publication date: 2019-06-20
Also published as: CN107961213A

Abstract

A black phosphorus-based hydrogel near-infrared light-controllable drug release system, comprising an agarose hydrogel carrier, and black phosphorus nanoflakes and an anticancer drug loaded in the agarose hydrogel carrier. The black phosphorus-based hydrogel near-infrared light-controllable drug delivery system has a near-infrared light response, and can transform from a gel state to a sol state in vivo under near-infrared light irradiation, thereby achieving local controllable drug release, effectively killing tumor cells at lesion sites. Further, the drug release system has controllable degradation characteristics, and has extremely high clinical value for the treatment of cancer. Also provided is a method for preparing the black phosphorus-based hydrogel near-infrared light-controllable drug release system.

Description

Black phosphorus based hydrogel near-infrared light controllable drug release system and preparation method thereof

Technical field

The invention relates to the technical field of biomedical nano materials, in particular to a black phosphorus-based hydrogel near-infrared light controllable drug release system and a preparation method thereof.

Background technique

Cancer seriously jeopardizes human life and health, and current clinical treatment for cancer, whether it is chemotherapy, surgery or radiation therapy, has great side effects on the body, and it is difficult to use any of the above methods after malignant metastasis Completely cured. Although a large amount of human, material and financial resources have been invested in cancer research, the progress is very limited, and the effective treatment of cancer is still a great test for human beings.

Studies have shown that the application of biomacromolecules and nanotechnology to the field of cancer diagnosis and treatment has broad prospects and clinical value. Among them, the hydrogel drug carrier with light-controlled release is a new type of cancer treatment method, which uses a laser to control the release of the drug, and locally distributes the lesion portion, and the excitation light for the illumination generally adopts near-infrared light. It is a non-invasive treatment for cancer that effectively penetrates normal human tissues and reaches cancer sites, greatly reducing damage to normal tissues. However, photo-sensitive nanoparticles (such as gold nanoparticles) currently used for photo-controlled release have low photothermal conversion efficiency and are not degradable, which brings difficulties to clinical application.

Recent studies have found that black phosphorus two-dimensional materials have great potential for application in biomedical fields, especially cancer treatment, due to their low toxicity, high biocompatibility, high extinction coefficient and high photothermal conversion efficiency. It is necessary to develop a black phosphorus-based hydrogel light-controlled drug delivery system to solve the problem of the clinical application of the existing hydrogel drug carrier.

Summary of the invention

In view of this, the present invention provides a black phosphorus-based hydrogel near-infrared light controllable drug delivery system having a near-infrared light response, which can achieve a transition from a gel state to a sol state by near-infrared light irradiation. Thereby achieving local photo-controlled release, effectively killing tumor cells in the lesion site, and at the same time having controllable degradation characteristics.

Specifically, in a first aspect, the present invention provides a black phosphorus-based hydrogel near-infrared light controllable drug delivery system comprising an agarose hydrogel carrier and black phosphorus supported in the agarose hydrogel carrier Nanoflakes and anticancer drugs.

The near-infrared light controllable drug delivery system provided by the invention uses agarose hydrogel as a drug controlled release carrier and black phosphorus as a photosensitizer. Since black phosphorus has a very high photothermal conversion efficiency, it acts in near-infrared light. Under the black phosphorus, a large amount of heat will be generated to dissolve the gelled agarose hydrogel in a sol state, thereby achieving controlled release of the anticancer drug, and the black phosphorus itself is degraded under the action of high intensity near-infrared light, so The inventive drug delivery system can simultaneously achieve controlled degradation of the drug carrier and the photosensitizer, and thus is expected to significantly improve the clinical efficacy of cancer treatment.

In the present invention, the agarose hydrogel carrier has a sol temperature of 40 ° C to 50 ° C, and the drug delivery system is in a gel state at 40 ° C or lower and a sol state at 40 ° C to 50 ° C. Specifically, the sol temperature may be 40 ° C, 42 ° C, 45 ° C, 48 ° C, 50 ° C. Selecting agarose with a lower sol temperature can make the drug delivery system gelatinous when there is no near-infrared light, and bind the anticancer drug and black phosphorus to facilitate local administration to the lesion. At the same time, the utilization rate of anticancer drugs is improved, and the damage of the anti-cancer drugs to normal tissue cells is avoided; on the other hand, the heat generated by the photothermal conversion effect of the black phosphorus nanosheets can be made by the drug delivery system when the near-infrared light is applied. Dissolve to achieve photo-controlled release in vivo.

In the present invention, in the drug delivery system, the content of the black phosphorus nanoflakes is 0.01-1 mg/mL, and the mass content of the anticancer drug is 0.01-1 mg/mL. Further, the content of the black phosphorus nanoflakes is 0.2-0.5 mg/mL, and the mass content of the anticancer drug is 0.2-0.5 mg/mL. The suitable black phosphorus nanosheet content is beneficial to improve the stability and controllable drug release capacity of the near infrared light controllable drug delivery system. The quality content of anticancer drugs can be reasonably set according to the specific anticancer drug type and dosage requirements.

In the present invention, the agarose hydrogel carrier is composed of agarose and water, and has an interwoven network structure. The agarose hydrogel carrier has a mass percentage of agarose of 0.5% to 2%, further, agarose The mass content is from 0.8% to 1.5% or from 1.0% to 1.2%. The mass content of agarose directly affects the mesh size and mechanical strength of the gel.

In the present invention, the black phosphorus nanoflakes have a length to width dimension of 50 nm to 200 nm; and the black phosphorus nanoflakes have a thickness of 1 nm to 5 nm. Alternatively, the black phosphorus nanoflakes have a size of 50 nm to 150 nm, 100 nm to 150 nm, 120 nm to 180 nm, and 160 nm to 200 nm. Alternatively, the thickness is 1-3 nm or 2-4 nm. Suitable black phosphorus nanosheets have a wide and wide size and thickness which facilitates their uniform dispersion in agarose hydrogel and absorption of near-infrared radiation.

Since the surface of the black phosphorus nanosheet has strong electronegativity, the anticancer drug is partially adsorbed on the surface of the black phosphorus nanosheet, and partially dispersed in the network structure formed by the agarose hydrogel carrier.

In the present invention, the surface of the black phosphorus nanoflake is coated with polyethylene glycol amine, and the mass ratio of the black phosphorus nanoflake to the polyethylene glycol amine is 1:0.5-2. Further, the mass ratio of the black phosphorus nanoflakes to the polyethylene glycol amine is 1:0.8-1.5 or 1:1-1.2. The polyethylene glycol amine includes methyl polyethylene glycol amine (CH ₃ -PEG-NH ₂ ), methoxy polyethylene glycol amine (CH ₃ O-PEG-NH ₂ , abbreviated as mPEG-NH ₂ ) And at least one of polyethylene glycol diamine (NH ₂ -PEG-NH ₂ ). The polyethylene glycol amine is adsorbed on the surface of the black phosphorus nanoflake by electrostatic attraction, and the polyethylene glycol amine has a weight average molecular weight of 2,000 to 30,000. Polyethylene glycol amine can improve the biocompatibility of black phosphorus nanosheets, effectively avoid the aggregation of black phosphorus nanosheets and improve the stability of black phosphorus nanosheets in aqueous solution, so that black phosphorus nanosheets can be uniformly and stably dispersed in the solution. In the hydrogel carrier, a good photo-controlled release is achieved.

The anticancer drug includes a currently used drug for treating cancer, such as doxorubicin.

The size of the black phosphorus-based hydrogel near-infrared light controllable drug delivery system of the present invention may vary depending on the actual application environment, and the volume may range from micro-nano to centimeter. The black phosphorus-based hydrogel near-infrared light controllable drug release system of the invention is solid at normal temperature. When injected in vivo, it is heated to transform into a sol state, and is rapidly transformed into a physiological environment temperature after being injected into the body. In the gelled state, it is subsequently converted into a sol state by the action of near-infrared light to achieve drug release.

In the present invention, the black phosphorus nanoflakes and the agarose have good biocompatibility, can be excreted by biodegradation or normal physiological routes, have no toxic side effects on the organism, and have high biosafety.

The black phosphorus-based hydrogel near-infrared light controllable drug delivery system provided by the first aspect of the invention has near-infrared light (700-1500 nm) response, and has photothermal heat killing tumor and chemotherapy drug with black phosphorescent material The efficacy of chemotherapy in the treatment of tumors has a very high clinical value for the treatment of cancer (such as breast cancer).

In a second aspect, the present invention provides a method for preparing a black phosphorus-based hydrogel near-infrared light controllable drug delivery system, comprising the steps of:

Providing a black phosphorus nanosheet, dispersing the black phosphorus nanosheet into an aqueous phase to obtain a black phosphorus nanosheet dispersion; adding an anticancer drug to the dispersion, uniformly mixing to obtain a mixed solution, and heating the mixed solution At 50-70 ° C, agarose is added and cooled to form a hydrogel, which is a black phosphorus-based hydrogel near-infrared light controllable drug delivery system.

In the present invention, the black phosphorus nanoflakes have a length to width dimension of 50 nm to 200 nm; and the black phosphorus nanoflakes have a thickness of 1 nm to 5 nm. Alternatively, the black phosphorus nanoflakes have a size of 50 nm to 150 nm, 100 nm to 150 nm, 120 nm to 180 nm, and 160 nm to 200 nm. Alternatively, the thickness is 1-3 nm or 2-4 nm. The method for obtaining the black phosphorus nanosheet is not limited. For example, the black phosphorus may be used as a raw material, and the solution is prepared by solution stripping and probe ultrasonication, and collected and purified by centrifugal tube centrifugation. The ultrasonic time is 12-18 hours, the ultrasonic process of the probe is continuous for 45 seconds - 1 hour, and the waiting period is 15 seconds - 1 hour, the power amplifier is 20% - 30%, and the centrifugation rate is 1000 rpm. - 2000 rpm, time 6-15 minutes, temperature 4 °C.

In the present invention, the temperature of the heating may be specifically determined according to the sol temperature of the agarose, and may be, for example, 50 ° C, 60 ° C, 70 ° C or the like. The agarose has a sol temperature of 40 ° C to 50 ° C, and the drug delivery system is in a gel state below 40 ° C, and is converted to a sol state at 40 ° C to 50 ° C. Specifically, the sol temperature may be 40 ° C, 42 ° C, 45 ° C, 48 ° C, 50 ° C.

In the present invention, in the drug delivery system, the content of the black phosphorus nanoflakes is 0.01-1 mg/mL, and the mass content of the anticancer drug is 0.01-1 mg/mL. Further, the content of the black phosphorus nanoflakes is 0.2-0.5 mg/mL, and the mass content of the anticancer drug is 0.2-0.5 mg/mL.

In the present invention, the agarose hydrogel has a mass content of agarose of 0.5% to 2%, and further, the agarose has a mass content of 0.8% to 1.5% or 1.0% to 1.2%.

In the present invention, the anticancer drug includes a currently used drug for treating cancer, such as doxorubicin.

In the present invention, before the addition of the anticancer drug, further comprising adding polyethylene glycol amine to the black phosphorus nanosheet dispersion, and obtaining a polyethylene glycol amine package under stirring or ultrasonic combined stirring. Covered black phosphorus nanoflakes. The agitation speed is from 800 rpm to 1200 rpm for a duration of 2-4 hours. The ultrasound has a frequency of 3000-4500 Hz and a duration of 0.5-2 hours. The sonication and agitation may be performed sequentially, for example, by first ultrasonicing for 0.5 hours and then for 3 hours. The polyethylene glycol amine includes methyl polyethylene glycol amine (CH ₃ -PEG-NH ₂ ), methoxy polyethylene glycol amine (CH ₃ O-PEG-NH ₂ , abbreviated as mPEG-NH ₂ ) And at least one of polyethylene glycol diamine (NH ₂ -PEG-NH ₂ ). The polyethylene glycol amine has a weight average molecular weight of from 2,000 to 30,000.

The preparation method of the black phosphorus-based hydrogel near-infrared light controllable drug release system provided by the second aspect of the invention is simple and easy to operate, and is suitable for industrial production.

DRAWINGS

1 is a schematic structural view of a black phosphorus-based hydrogel near-infrared light controllable drug release system prepared in Example 1 of the present invention;

2 is a schematic structural view of a polyethylene glycol amine-coated black phosphorus nanosheet prepared in Example 1 of the present invention;

3 is an EDS (Energy Dispersive Spectrometer) diagram of a polyethylene glycol amine-coated black phosphorus nanosheet prepared in Example 1 of the present invention;

4 is a schematic diagram of release and degradation of a black phosphorus-based hydrogel near-infrared light controllable drug release system according to an embodiment of the present invention;

5 is an in vitro fluorescence imaging of a black phosphorus-based hydrogel near-infrared light controlled release drug system prepared in Example 1 of the present invention in Hela cells at different times of illumination;

6 is a drug release curve of a black phosphorus-based hydrogel near-infrared light controllable drug release system according to an embodiment of the present invention;

7 is a cytotoxicity result of a black phosphorus-based hydrogel near-infrared light controllable drug release system prepared in Example 1 of the present invention in different cancer cells (Hela, MCF-7, A549, and PC3);

Figure 8 is a graph showing the results of changes in cell viability over time under different gel systems.

Detailed ways

The following are the preferred embodiments of the embodiments of the present invention, and it should be noted that those skilled in the art can make some improvements and refinements without departing from the principles of the embodiments of the present invention. And retouching is also considered to be the scope of protection of the embodiments of the present invention.

Example 1

A method for preparing a hydrogel near-infrared light controllable drug release system based on black phosphorus, comprising the following steps:

(1) Preparation of black phosphorus nanosheets by solution stripping and probe ultrasonication: 50mg bulk black phosphorus material was placed in 100mL ultrapure water for probe sonication, and the ultrasonic time of the probe was 12 hours. The process is continuous ultrasonic for 45 seconds, waiting for 15 seconds for one cycle, and the power amplifier is 20%; after the end of the ultrasound, the brown black stripping solution is placed in a centrifuge tube, centrifuged at 1000 rpm for 10 minutes, the temperature is 4 ° C, and the precipitate is not peeled off. Blocky black phosphorus, and carefully separate the precipitated black phosphorus and black phosphorus nanosheets in the supernatant to further purify the black phosphorus nanosheets;

(2) Dispersing the black phosphorus nanosheets obtained above into water, and sequentially coating the surface of the black phosphorus nanosheet with polyethylene glycol amine by ultrasonic and magnetic stirring to obtain black containing polyethylene glycol amine coating. a solution of phosphorus nanosheets; wherein the mass ratio of black phosphorus nanosheets to polyethylene glycol amine is 1:2, the frequency of ultrasonication is 4000HZ, the duration is 2 hours, the magnetic stirring speed is 800 rpm, and the duration is 4 hours; The polyethylene glycol amine is at least one of methyl polyethylene glycol amine, methoxy polyethylene glycol amine and polyethylene glycol diamine, and the weight average molecular weight of the polyethylene glycol amine is 2000-30000;

(3) adding the anticancer drug doxorubicin to the solution obtained by the above-mentioned polyethylene glycolamine-coated black phosphorus nanoflake to obtain a mixed solution;

(4) heating the mixed solution to 50 ° C, and then adding agarose having a sol temperature of 40 ° C, until the agarose is completely dissolved, and cooling to form a hydrogel, thereby obtaining a black phosphorus-based hydrogel near-infrared Light controlled release drug system.

1 is a schematic view showing the structure of a black phosphorus-based hydrogel near-infrared light controllable drug release system prepared in Example 1 of the present invention, comprising an agarose hydrogel carrier 10 uniformly distributed in the agarose hydrogel carrier 10; Black phosphorus nanoflakes 20 and anticancer drugs 30. The black phosphorus-based hydrogel near-infrared light controllable drug release system prepared in this embodiment has a black phosphorus nanosheet content of 0.5 mg/mL (corresponding to 500 ppm), and agarose mass concentration in the agarose hydrogel carrier. At 1%, the mass content of doxorubicin was 0.1 mg/mL.

FIG. 2 and FIG. 3 are respectively a structural diagram and an EDS spectrum of the polyethylene glycol amine-coated black phosphorus nanosheet prepared in the step (2) in the first embodiment of the present invention; wherein 21 is a black phosphorus nanosheet, 22 is a polyethylene glycol amine. It can be known from the peak positions of C, O, and N in Fig. 3 that the black phosphorus is coated with polyethylene glycol amine.

The black phosphorus-based hydrogel near-infrared light controllable drug release system prepared by the embodiment of the invention can achieve local administration to the lesion site, and after the administration is completed, the laser is excited by the 808 nm near-infrared band, and the black phosphorus nanosheet will be Exerting its superior photothermal conversion performance, providing a large amount of heat to soften the gelled agarose hydrogel, increasing the diffusion coefficient of the anticancer drug in the hydrogel, thereby rapidly releasing the drug; and then further increasing the laser power, such as from The initial 1W is increased to 2W, which dissolves the hydrogel, accelerates its degradation, and accelerates the degradation of the internal black phosphorus nanosheets, thereby achieving controlled release of the anticancer drug, and finally effectively killing the cancer cells at the lesion site. 4 is a schematic diagram showing the release and degradation of a black phosphorus-based hydrogel near-infrared light controllable drug release system prepared according to an embodiment of the present invention.

In Fig. 5, a), b), c), and d) are respectively a black phosphorus-based hydrogel near-infrared light controllable drug release system prepared in Example 1 of the present invention, in Hela cells, in vitro at different times of illumination. Cellular fluorescence imaging. From the results of different light hours of 0min, 5min, 10min, 15min in the figure, it can be seen that with the increase of illumination time, the more doxorubicin released, the number of normal cancer cells is decreasing, after 15min illumination, the cancer cells are basically All died.

6 is a drug release curve of a black phosphorus-based hydrogel near-infrared light controllable drug release system according to Example 1 of the present invention as a function of temperature. In the figure, curve 1 represents a temperature curve, curve 2 represents the concentration of the drug released into the solution, on means heating, and off means stopping heating. As can be seen from the results in the figure, each heating and heating will cause the drug to be released quickly, and when the heating is stopped, the drug release rate is very low.

Example 2

(1) Preparation of black phosphorus nanosheets by solution stripping and probe ultrasonication: 50 mg of bulk black phosphorus material was placed in 100 mL of ultrapure water for probe sonication, and the ultrasonic time of the probe was 18 hours. The process is continuous ultrasound for 1 hour, waiting for 1 hour for one cycle, and the power amplifier is 20%. After the end of the ultrasound, the brown-black stripping solution was placed in a centrifuge tube, centrifuged at 2000 rpm for 6 minutes, the temperature was 4 ° C, and the un-stripped block-shaped black phosphorus was precipitated, and the precipitated block black phosphorus and the supernatant were carefully separated. Black phosphorus nanosheets for further purification of black phosphorus nanosheets;

(2) Dispersing the black phosphorus nanosheets obtained above into water, and sequentially coating the surface of the black phosphorus nanosheet with polyethylene glycol amine by ultrasonic and magnetic stirring to obtain black containing polyethylene glycol amine coating. a solution of phosphorus nanosheets; wherein the mass ratio of black phosphorus nanosheets to polyethylene glycol amine is 1:1, the frequency of ultrasonication is 3500 Hz, the duration is 0.5 hours, the magnetic stirring speed is 1000 rpm, and the duration is 4 hours; The polyethylene glycol amine is at least one of methyl polyethylene glycol amine, methoxy polyethylene glycol amine and polyethylene glycol diamine, and the weight average molecular weight of the polyethylene glycol amine is 2000-30000;

(4) heating the mixed solution to 60 ° C, and then adding agarose having a sol temperature of 45 ° C, until the agarose is completely dissolved, and cooling to form a hydrogel, thereby obtaining a black phosphorus-based hydrogel near-infrared Light controlled release drug system. The black phosphorus-based hydrogel near infrared light controllable drug release system prepared in this embodiment has a black phosphorus nanosheet content of 1 mg/mL, and the agarose hydrogel carrier has a mass concentration of agarose of 0.5%. The mass content of the prime is 0.1 mg/mL.

Example 3

(1) Preparation of black phosphorus nanosheets by solution stripping combined with probe ultrasonic method, taking 50mg of block black phosphorus material, placing it in 100mL ultrapure water, performing probe ultrasonication, and the ultrasonic time of the probe ultrasonic method is 16 hours. The process is continuous ultrasound for 1 hour, waiting for 1 hour for one cycle, and the power amplifier is 25%. After the end of the ultrasound, the brown-black peeling solution was placed in a centrifuge tube, centrifuged at 1000 rpm for 15 minutes, the temperature was 4 ° C, and the un-stripped block-shaped black phosphorus was precipitated, and the precipitated block black phosphorus and the supernatant were carefully separated. Black phosphorus nanosheets for further purification of black phosphorus nanosheets;

(2) Dispersing the black phosphorus nanosheets obtained above into water, and sequentially coating the surface of the black phosphorus nanosheet with polyethylene glycol amine by ultrasonic and magnetic stirring to obtain black containing polyethylene glycol amine coating. a solution of phosphorus nanoflakes; wherein the mass ratio of black phosphorus nanoflakes to polyethylene glycol amine is 1:0.5, the frequency of ultrasonication is 4000HZ, the duration is 1 hour, the magnetic stirring speed is 1200 rpm, and the duration is 4 hours; The polyethylene glycol amine is at least one of methyl polyethylene glycol amine, methoxy polyethylene glycol amine and polyethylene glycol diamine, and the weight average molecular weight of the polyethylene glycol amine is 2000-30000;

(4) heating the mixed solution to 70 ° C, and then adding agarose having a sol temperature of 50 ° C, until the agarose is completely dissolved, and cooling to form a hydrogel, thereby obtaining a black phosphorus-based hydrogel near-infrared Light controlled release drug system. The black phosphorus-based hydrogel near-infrared light controllable drug release system prepared in this embodiment has a mass concentration of 0.2 mg/mL of black phosphorus nanosheets and a mass concentration of agarose of 2% in the agarose hydrogel carrier. The mass content of doxorubicin was 0.5 mg/mL.

Example 4

(1) Preparation of black phosphorus nanosheets by solution stripping combined with probe ultrasonic method, taking 50 mg of bulk black phosphorus material, placing it in 100 mL of ultrapure water, and performing probe ultrasonication. The ultrasonic time of the probe ultrasonic method is 14 hours. The process is continuous ultrasound for 0.5 hours, waiting for 0.5 hours for one cycle, and the power amplifier is 30%. After the end of the ultrasound, the brown-black peeling solution was placed in a centrifuge tube, centrifuged at 2000 rpm for 10 minutes, the temperature was 4 ° C, and the un-stripped block-shaped black phosphorus was precipitated, and the precipitated block black phosphorus and the supernatant were carefully separated. Black phosphorus nanosheets for further purification of black phosphorus nanosheets;

(2) Dispersing the black phosphorus nanosheets obtained above into water, and sequentially coating the surface of the black phosphorus nanosheet with polyethylene glycol amine by ultrasonic and magnetic stirring to obtain black containing polyethylene glycol amine coating. a solution of phosphorus nanosheets; wherein the mass ratio of black phosphorus nanosheets to polyethylene glycol amine is 1:1, the frequency of ultrasonication is 4500 Hz, the duration is 1.5 hours, the magnetic stirring speed is 1000 rpm, and the duration is 3 hours; The polyethylene glycol amine is at least one of methyl polyethylene glycol amine, methoxy polyethylene glycol amine and polyethylene glycol diamine, and the weight average molecular weight of the polyethylene glycol amine is 2000-30000;

(4) The mixed solution is heated to 55 ° C, and then agarose having a sol temperature of 45 ° C is added thereto, and the agarose is completely dissolved, and after cooling, a hydrogel is formed to obtain a black phosphorus-based hydrogel near-infrared. Light controlled release drug system. The black phosphorus-based hydrogel near infrared light controllable drug release system prepared in this embodiment has a mass concentration of 0.05 mg/mL of black phosphorus nanosheets and a mass concentration of agarose of 1.5% in the agarose hydrogel carrier. The mass content of doxorubicin is 1 mg/mL.

7 is a graph showing the toxicity results of a black phosphorus-based hydrogel near-infrared light controllable drug release system in different cancer cells (A549, Hela, PC3, and MCF-7) prepared according to an embodiment of the present invention; There were four groups of experiments with different concentrations of black phosphorus (0 mg/mL, 0.05 mg/mL, 0.2 mg/mL, 0.5 mg/mL). In each group of experiments, each column from left to right was recorded as 1, 2 in turn. 3, 4, where 1 represents A549, 2 represents Hela, 3 represents PC3, and 4 represents MCF-7. It can be seen from the figure that the black phosphorus-based hydrogel near-infrared light controllable drug delivery system of the embodiment of the invention does not have cytotoxicity under the condition of no laser irradiation, and has good biosafety and no toxic and side effects.

Figure 8 is a graph showing the results of changes in cell viability over time under different gel systems. The ordinate represents cell activity, 100% means the highest cell activity, 0 means all cell apoptosis; the abscissa represents the time when cells are treated by different gel systems, and the specific time is 0min, 5min, 10min, 15min respectively. The results of the four sets of experiments, in each set of results, from left to right, each column is sequentially recorded as 1, 2, 3, 4, where 1 represents the case of only laser irradiation; 2 represents the black based on the embodiment 1 of the present invention. Phosphorus hydrogel near-infrared light controllable drug delivery system, but no laser irradiation; 3 represents the case of adding black phosphorus-based hydrogel near-infrared light controllable drug delivery system of Example 1 of the present invention (black phosphorus The concentration is 0.5 mg/mL, the agarose mass content is 1%); 4 represents the case of adding the black phosphorus-based hydrogel near-infrared light controllable drug delivery system of Example 2 of the present invention (the black phosphorus concentration is 1 mg/mL). , the agarose mass content is 0.5%). The results in the figure show that the

experimental groups

3 and 4 of the black phosphorus-based hydrogel near-infrared light controllable drug delivery system provided by the embodiments of the present invention have significantly reduced cancer cells over time, and the experimental group 4 The effect is better than experimental group 3.

Claims

A black phosphorus-based hydrogel near-infrared light controllable drug delivery system comprising an agarose hydrogel carrier, and a black phosphorus nanoflake and an anticancer drug supported in the agarose hydrogel carrier.
The black phosphorus-based hydrogel near-infrared light controllable drug delivery system according to claim 1, wherein the agarose hydrogel carrier has a sol temperature of 40 ° C to 50 ° C, and the drug delivery system is Below 40 ° C is a gel state, and at 40 ° C - 50 ° C is converted to a sol state.
The black phosphorus-based hydrogel near infrared light controllable drug delivery system according to claim 1, wherein the content of the black phosphorus nanosheet is 0.01 mg/mL-1 mg/in the drug delivery system. The mass of the anticancer drug is from 0.01 mg/mL to 1 mg/mL.
The black phosphorus-based hydrogel near-infrared light controllable drug delivery system according to claim 1, wherein the agarose hydrogel carrier has a mass content of agarose of 0.5% to 2%.
The black phosphorus-based hydrogel near infrared light controllable drug delivery system according to claim 1, wherein the black phosphorus nanosheet has a length to width dimension of 50 nm to 200 nm; and the thickness of the black phosphorus nanosheet It is from 1 nm to 5 nm.
The black phosphorus-based hydrogel near infrared light controllable drug delivery system according to claim 1, wherein the anticancer drug is partially adsorbed on the surface of the black phosphorus nanosheet, and partially dispersed on the agar. The sugar hydrogel carrier is formed in a network structure.
The black phosphorus-based hydrogel near infrared light controllable drug delivery system according to claim 1, wherein the black phosphorus nanosheet is coated with polyethylene glycol amine, the black phosphorus nanosheet and The mass ratio of polyethylene glycol amine is 1:0.5-2.
The black phosphorus-based hydrogel near infrared light controllable drug delivery system according to claim 7, wherein the polyethylene glycol amine is adsorbed on the surface of the black phosphorus nanosheet by electrostatic attraction, the polymerization The ethylene glycol amine includes at least one of methyl polyethylene glycol amine, methoxy polyethylene glycol amine, and polyethylene glycol diamine, and the polyethylene glycol amine has a weight average molecular weight of 2,000 to 30,000.
The black phosphorus-based hydrogel near-infrared light controllable drug delivery system according to claim 1, wherein the anticancer drug comprises doxorubicin.
A method for preparing a hydrogel near infrared light controllable drug release system based on black phosphorus, characterized in that the method comprises the following steps:

Providing a black phosphorus nanosheet, dispersing the black phosphorus nanosheet into an aqueous phase to obtain a black phosphorus nanosheet dispersion; adding an anticancer drug to the dispersion, uniformly mixing to obtain a mixed solution, and heating the mixed solution At 50-70 ° C, agarose is added and cooled to form a hydrogel, which is a black phosphorus-based hydrogel near-infrared light controllable drug delivery system.
The preparation method according to claim 10, further comprising adding polyethylene glycol amine to said black phosphorus nanosheet dispersion before adding said anticancer drug, and obtaining polyethylene glycol under stirring Alcohol amine coated black phosphorus nanoflakes.